1,3-Azole-containing amino acids have utility as analogues of natural amino acids for incorporation into biologically active molecules. In particular, they are constituent parts of many biologically active peptides and are useful in preparing antimicrobial agents. Currently, no general method for their synthesis exists.
Saeed and Young have described the synthesis of L-beta-hydroxy amino acids using an enzymatic method (Saeed, A; Young, D. W; Tetr. 1992, 48, 2507-2514). Their method does not produce the 1,3-azole-containing amino acids synthesized by the present inventive method, and their route gives a mixture of isomeric forms.
Kimura et al. report another enzymatic synthesis of beta-hydroxy-amino acids. (Kimura, T. et al., J. Am. Chem. Soc. 1997 119, 11734-11742). Their synthesis, however, provides mixed stereochemistry at the beta-carbon.
Dalla Croce et al. report a stereoselective aldol addition of a chiral glycine enolate synthon (Dalla Croce, P. et al., Heterocycles, 2000, 52, 1337-1344). Their method, however, produces only moderate yields and they do not report synthesis of any 1,3-azole-containing acids.
Palian and Polt report synthesis of lipophilic beta-hydroxy amino acids (Palian, M; Polt, R., J. Org. Chem., 2001, 66, 7178-7183). These authors do not describe the methods of the present invention and they do not describe the synthesis of 1,3-azole-containing amino acids.
Zhao et al. reported oxidation of primary alcohols to carboxylic acids using TEMPO catalyst along with sodium chlorite and bleach (Zhao et al., J. Org. Chem., 1999, 64, 2564-2566). They did not apply their method, however, to produce beta-hydroxy amino acids.
Barma et al. reported an oxidative removal of the N,N-dimethylthiocarbamate group from alcohols (Barma et al., Org. Lett., 2003, 5, 4755-4757). These authors do not describe the synthesis of 1,3-azole-containing amino acids.
The Garner aldehydes (Garner, P. Tetr. Lett., 1984, 25, 5855-5858; Liang, X, et al., J. Chem. Soc. Perkin Trans. 1, 2001, 2136-2157), for which both the S and R configurations are commercially available, are configurationally stable under many reaction conditions that are typically employed for the elaboration of the aldehyde functionality. Lubell and Rapoport introduced the phenylfluorenyl-protected oxazolidone as a serinal equivalent similar to Garner's aldehyde, and the inclusion of the phenylfluorenyl moiety greatly stabilizes the configuration of the α-proton in products under basic conditions (Lubell, W; Rapoport, H; J. Org. Chem., 1989, 54, 3824-3831). It has seen only limited utility in organic synthesis and has been commented by Rapoport that the phenylfluorenyl group is known to be more acid-stable than the related trityl group for other substrates. Both of these substrates allow for the selective incorporation of nucleophiles into an intermediate for further derivatization.
Dondoni has utilized a variety of chiral, alpha-amino aldehydes as reactants in a condensation reaction with 2-trimethylsilylthiazole (Dondoni, A, et al., J. Org. Chem., 1990, 55, 1439-1446). The use of Garner's aldehyde furnished the best results in terms of yield and selectivity. Dondoni and others have generally utilized this thiazole chemistry as a method to incorporate a formyl group, rather than functionalize the portion of the molecule derived from Garner's aldehyde.
Thus, there is a need for a generalized method to synthesize 1,3-azole-containing amino acids